Primary central nervous system lymphomas (PCNSLs) are highly malignant non-Hodgkin�s lymphomas of the diffuse large B cell type (DLBCL) confined to the brain. PCNSL are targeted by ongoing somatic hypermutation and show molecular features of the late germinal center exit B-cell phenotype. However, PCNSL are impaired in their terminal differentiation as indicated by a lack of immunoglobulin class switching. The aim of the present study was characterize genetic alterations in PCNSL. Therefore, a series of 19 PCNSL was analyzed by use of the high-resolution 100K GeneChip® mapping assay. These identified frequent novel gains and losses in addition to previously described imbalances in PCNSL. Moreover, this platform allowed the simultaneous genotyping to detect loss of heterozygosity without changes in DNA copy number. Here, we confirmed chromosomal imbalances such as a recurrent loss of chromosomal arm 6q and parts of 4q, 6p, and 9p, trisomy 12, gains of 18q, 19q and chromosome X. Furthermore, we identified novel regions of chromosomal imbalances, which have not yet been described in PCNSL. The newly detected minimally aberrant regions involved deletions of 3p14.2, 8q12.1-q12.2, 10q23.1, 12p13.2, as well as gains of 7q21.3-22.1, and 9p21.1-p21.3. Some of the detected imbalances affected regions smaller than 200 bp. We also demonstrated for the first time regions with recurrent partial uniparental disomy (pUPD) in 6p and 9p. Various recurrent alterations affect genes, which are involved in the immune response, including HLA expression and regulation. Deletions in 6p21.32 compromised genes of the major histocompatibility complex (MHC) class 2 as well as the TAP1 and TAP2 genes, which are involved in assembling of MHC Class I antigens. The nuclear factor NFX1 in the region of gain of 9p21.1-p21.3 represses expression of HLA-DR and other genes of the MHC class II complex. These alterations may interfere with the immune response to tumor cells, which may be involved in the pathogenesis of PCNSL. Another set of aberrations affected genes, which are involved in the regulation of apoptosis. Deletion of the FAS(CD95) harbouring 10q23.21 can comprise the apoptosis induced by Fas ligands. Gains of the gene loci harbouring BCL2, MDM2, and BAG1 as well as a deregulation of BCL6 expression due to translocations leading to a promoter substitution of BCL6 may inhibit p53 mediated pro-apoptotic pathways. Recurrent deletions and pUPD affecting 9p21.3 potentially leading to inactivation of the tumor suppressor genes p15 and p16 may result in a deregulation of the cell cycle leading to ongoing mitosis. Remarkably, more than 50% of the PCNSL harboured a deletion in 6q21, where the BLIMP1 coding PRDM1 is located. BLIMP1 is one of the central regulators for terminal B cell differentiation. Thus, impaired BLIMP-1 function may block terminal differentiation of the tumor cells of PCNSL resulting in an arrest of the state of the highly proliferative GC phenotype. Furthermore. the frequent translocations involving the BCL6 and the IGH gene loci by long distance inverse PCR. Here, we identified four novel partner genes of BCL6. The translocations lead to a juxtaposition of the BCL6 with regulatory elements of IGH, IGL, and Histone1H4I, leading to a promoter substitution and deregulation of BCL6 expression. In one case, a deletion within 3q leads to a juxtaposition of BCL6 and LPP, which has not been described before, neither for PCNSL nor for other tumour entities. In conclusion, the present work contributes to the comprehension of new molecular aspects of the pathogenesis of PCNSL and suggests a potential for diagnostically and/or therapeutically relevant applications.